Cellular microvesicles (MVs) are a category of bi-layer lipid membrane biologic vesicles, ranging between 10-500 nm in diameter. They were first reported as early as in year 1967 and named “platelet dust” since they were derived from platelets, containing vesicles and promoting agglutination. In vitro studies have found that each of endothelial cells, vascular smooth muscle cells, platelets, leucocytes, lymphocytes, erythrocytes, and the like are all able to secret MVs. According to their source, MVs can be divided into two categories: exosomes and shedding vesicles. Exosomes are secreted in the manner of exocytosis with multi-vesicular bodies (MVBs) when cells are stimulated, and shedding vesicles are secreted by direct budding. Presently, different names are given to shedding vesicles secreted by different cells, for example, those from neutrophil granulocytes and monocytes are called ectosomes, and those from platelets are called microparticles.
Two cellular MV generation pathways are already known: cellular activation and apoptosis, but till now it is uncertain that whether the cellular MVs generated in these two pathways are similar in size, composition, and physiological functions or not. The membrane components of cellular MVs, mainly consisting of lipids and proteins, depend on source cells, while the internal components of the cellular MVs are yet unknown. It is predicted that the cellular MVs play a part in intercellular communication, receptor delivery, signal triggering or cellular contact, probably as well as in stress reaction, inflammation reaction and tissue regeneration of organ defense systems. However, the definite physiological functions of cellular MVs have not been investigated clearly up yet to now.
Micro-ribonucleic acids (microRNAs, miRNAs) have been a hot spot recently. They are a class of single stranded ribonucleic acid molecules that consist of about 19-23 nucleotides in length, locate in non-coding regions in the genome and are highly conserved in evolution. MiRNAs may regulate gene expression by inhibiting the translation of their target genes, and are closely related to many physiological actions of animals, such as individual development, tissue differentiation, cell apoptosis and energy metabolism, and etc., as well as to the occurrence and progression of various diseases. Since the discovery of lin-4 and let-7 involved in the regulation of timing development of nematodes, miRNAs have become a hot spot in the field of regulation of miRNA stability and protein translation and are selected as one of top 10 scientific breakthroughs of Science in year 2002 and 2003 successively. Now, it is predicted that the miRNAs can at least regulate 5,300 human genes, that is, 30% of all human genes. More and more miRNAs have been found in further research, wherein the relations between miRNAs and tumors are becoming an important point in primary study. It has been found that several miRNAs are closely related to chronic lymphocytic leukemia, lung cancer, breast cancer, and colon carcinoma by negative regulation of gene expression. Recently, it has been found that the expression levels of several miRNAs in both chronic lymphocytic leukemia and Burkitt's lymphoma are down-regulated to certain extents. Analysis on the expression of the miRNAs in human lung cancer and breast cancer tissues shows that the expression levels of several tissue-specific miRNAs vary relative to normal tissues. Other studies have also demonstrated that the miRNAs affect the occurrence and progression of cardiovascular diseases, including myocardial hypertrophy, heart failure, atherosclerosis and etc., and are closely related to metabolic diseases such as diabetes type II. These experimental results indicate that the expression of the miRNAs and the specificity variations thereof are inevitably related to the occurrence and progression of the diseases.
MiRNAs play a highly important role in gene post-transcriptional regulation, which indicates that the relation between miRNAs and diseases is: firstly, the variations of miRNAs may be the result of diseases, because the occurrence of diseases (cancers, for instance) will cause chromosome segments loss, gene mutation or sudden amplification of chromosome segments. If the miRNAs are located in such varied segments, their expression levels will vary tremendously. Secondly, the variations of miRNAs may be the cause of diseases, because the disease inhibition and promotion factors are probably the targets of miRNAs. When there are miRNA expression disorders, for example, when expression level of miRNAs that inhibit the disease promotion factors is down-regulated, or the expression level of the miRNAs that inhibit the disease inhibition factors is up-regulated, the down-stream gene expression will be altered and there comes pathway disorder, eventually causing the occurrence of the diseases. On the contrary, if the expression level of miRNAs that inhibit the disease promotion factors is up-regulated, or the expression level of miRNAs that inhibit the disease inhibitory factors is down-regulated, the down-regulation of a series of disease promotion factors will be caused, and thereby the occurrence or progression of diseases will be inhibited. Therefore, theoretically, miRNAs can be used not only as a novel class of disease markers—their specificity variations are necessarily related to the occurrence and progression of the diseases; but also potential drugs, the occurrence and progression of the diseases may be largely relieved by inhibiting the miRNAs whose expression levels are up or down-regulated during the disease progression. Therefore, it is rather significant for the prevention and/or treatment of various diseases to develop a drug that can regulate the miRNA content in patients, so as to up-regulate the disease inhibitory factors, or down-regulate the disease promotion factors.
In recent years, miRNA medicine has been a hot spot of pharmaceutical development. It has been proved that the progression of diseases could be inhibited or deferred by regulating the expression of certain miRNAs. For instance, highly expressed miR-206 in skeletal muscles could relieve the motor neuron injury or loss, which is achieved by improving and activating the regeneration of neuron connections between muscles, whereby can treat Amyotrophic lateral sclerosis (ALS). Similarly, HCV can be treated by down-regulating miR-122 expression in liver. Loss of miR-15 and miR-16 results in over-expression of Bal-2, which is the key cause of chronic lymphatic leukemia (CLL), and thus up-regulating the expression of miR-15 and miR-16 shall be an effective way to cure CLL.
Although the research and exploration on miRNA medicine has got many achievements, some problems still hinder their practical use, with the biggest one being the insufficient efficiency and inadequate ability of targeted drug delivery. Presently, the miRNA carriers mainly include liposome, nanocapsules (or nanoparticles), β-cyclodextrin inclusion compound, and etc. Although they can prolong the drug retention in vivo and promote drug absorption to some extent, their targeted ability and efficiency in drug delivery are still unsatisfactory. Virus vectors can also promote drug delivery in vivo, but their potential threat to living beings restrains their application in miRNA drug delivery. Further research shall be done on the effective drug administration on human beings or animals, insuring both effective and secure drug delivery to the target organs/tissues.